Mirapex ER® tablets are indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease.
2 DOSAGE AND ADMINISTRATION
General Dosing Considerations
Mirapex ER tablets are taken orally once daily, with or without food.
Mirapex ER tablets must be swallowed whole and must not be chewed, crushed, or divided.
If a significant interruption in therapy with Mirapex ER tablets has occurred, re-titration of therapy may be warranted.
Dosing for Parkinson's Disease
The starting dose is 0.375 mg given once per day. Based on efficacy and tolerability, dosages may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day.
In clinical trials, dosage was initiated at 0.375 mg/day and gradually titrated based on individual therapeutic response and tolerability. Doses greater than 4.5 mg/day have not been studied in clinical trials. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment [see Clinical Studies (14)].
Due to the flexible dose design used in clinical trials, specific dose-response information could not be determined [see Clinical Studies (14)].
When discontinuing therapy with Mirapex ER, taper the dose gradually over a period of one week. In some studies with immediate-release pramipexole tablets, however, abrupt discontinuation was uneventful.
Dosing in Patients with Renal Impairment
The elimination of pramipexole is dependent on renal function [see Clinical Pharmacology (12.3)]. Patients with mild renal impairment (a creatinine clearance above 50 mL/min) require no reduction in daily dose.
In patients with moderate renal impairment (creatinine clearance between 30 and 50 mL/min), Mirapex ER tablets should initially be taken every other day. Caution should be exercised and careful assessment of therapeutic response and tolerability should be made before increasing to daily dosing after one week, and before any additional titration in 0.375 mg increments up to 2.25 mg per day. Dose adjustment should occur no more frequently than at weekly intervals.
Mirapex ER tablets have not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min) or patients on hemodialysis, and are not recommended in these patients.
Switching from Immediate-Release Pramipexole Tablets to Mirapex ER
Patients may be switched overnight from immediate-release pramipexole tablets to Mirapex ER tablets at the same daily dose. When switching between immediate-release pramipexole tablets and Mirapex ER tablets, patients should be monitored to determine if dosage adjustment is necessary.
3 DOSAGE FORMS AND STRENGTHS
0.375 mg white to off-white, round, bevel-edged, extended-release tablets debossed with "ER" on one side and "0.375" on the other side
0.75 mg white to off-white, round, bevel-edged, extended-release tablets debossed with "ER" on one side and "0.75" on the other side
1.5 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "1.5" on the other side
2.25 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "2.25" on the other side
3 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "3.0" on the other side
3.75 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "3.75" on the other side
4.5 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "4.5" on the other side
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
Falling Asleep During Activities of Daily Living
Patients treated with pramipexole have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on pramipexole tablets, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as one year after the initiation of treatment. In placebo-controlled clinical trials in Parkinson's disease, the sudden onset of sleep or sleep attacks were reported in 8 of 387 (2%) patients treated with Mirapex ER tablets compared to 2 of 281 (1%) patients on placebo.
In early Parkinson’s disease, somnolence was reported in 36% of 223 patients treated with Mirapex ER, median dose 3.0 mg/day, compared to 15% of 103 patients on placebo. In advanced Parkinson’s disease, somnolence was reported in 15% of 164 patients treated with Mirapex ER tablets, median dose 3 mg/day, compared to 16% of 178 patients on placebo. Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
Before initiating treatment with Mirapex ER tablets, advise patients of the potential to develop drowsiness, and specifically ask about factors that may increase the risk such as the use of concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine) [see Clinical Pharmacology (12.3)]. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), Mirapex ER tablets should ordinarily be discontinued. If a decision is made to continue Mirapex ER tablets, advise patients not to drive and to avoid other potentially dangerous activities. While dose reduction reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
Symptomatic Orthostatic Hypotension
Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, Parkinson's disease patients being treated with dopaminergic agonists, including Mirapex ER, ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk [see Patient Counseling Information (17.5)]. In placebo-controlled clinical trials in Parkinson’s disease, symptomatic orthostatic hypotension was reported in 10 of 387 (3%) patients treated with Mirapex ER tablets compared to 3 of 281 (1%) patients on placebo. One patient of 387 on Mirapex ER tablets discontinued treatment due to hypotension.
Impulse Control/Compulsive Behaviors
Case reports and the results of cross-sectional studies suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including Mirapex ER, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with Mirapex ER. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Mirapex ER [see Patient Counseling Information (17.3)].
A total of 1056 patients with Parkinson’s disease who participated in two Mirapex ER placebo-controlled studies of up to 33 weeks duration were specifically asked at each visit about the occurrence of these symptoms. A total of 14 of 387 (4%) treated with Mirapex ER tablets, 12 of 388 (3%) treated with immediate-release pramipexole tablets, and 4 of 281 (1%) treated with placebo reported compulsive behaviors, including pathological gambling, hypersexuality, and/or compulsive buying.
Hallucinations
In placebo-controlled clinical trials in Parkinson's disease, hallucinations (visual or auditory or mixed) were reported in 25 of 387 (6%) patients treated with Mirapex ER tablets compared to 5 of 281 (2%) patients receiving placebo. Hallucinations led to discontinuation of treatment in 5 of 387 (1%) patients on Mirapex ER tablets.
Age appears to increase the risk of hallucinations attributable to pramipexole. In placebo-controlled clinical trials in Parkinson’s disease, hallucinations were reported in 15 of 162 (9%) patients ≥65 years of age taking Mirapex ER tablets compared to 10 of 225 (4%) patients <65 years of age taking Mirapex ER tablets.
Dyskinesia
Mirapex ER tablets may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia.
Renal Impairment
The elimination of pramipexole is dependent on renal function [see Clinical Pharmacology (12.3)]. Patients with mild renal impairment (a creatinine clearance above 50 mL/min) require no reduction in daily dose. Mirapex ER tablets have not been studied in patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) or on hemodialysis [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Rhabdomyolysis
In the clinical development program for immediate-release pramipexole tablets, a single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson's disease. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication.
Advise patients to contact a physician if they experience any unexplained muscle pain, tenderness, or weakness, as these may be symptoms of rhabdomyolysis.
Retinal Pathology in Rat
Animal Data
Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in a 2-year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect for humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved [see Nonclinical Toxicology (13.2)].
Events Reported with Dopaminergic Therapy
Although the events enumerated below may not have been reported with the use of pramipexole in its development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date.
Withdrawal-Emergent Hyperpyrexia and Confusion
Although not reported with pramipexole in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in anti-Parkinsonian therapy.
Fibrotic Complications
Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.
Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, non-ergot derived dopamine agonists can cause them is unknown.
Cases of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been reported in the postmarketing experience with immediate-release pramipexole tablets. While the evidence is not sufficient to establish a causal relationship between pramipexole and these fibrotic complications, a contribution of pramipexole cannot be completely ruled out.
Melanoma
Epidemiologic studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the observed increased risk was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Mirapex ER tablets for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
6 ADVERSE REACTIONS
The following are discussed in greater detail in other sections of the labeling:
- Falling Asleep During Activities of Daily Living [see Warnings and Precautions (5.1)]
- Symptomatic Orthostatic Hypotension [see Warnings and Precautions (5.2)]
- Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.3)]
- Hallucinations [see Warnings and Precautions (5.4)]
- Dyskinesia [see Warnings and Precautions (5.5)]
- Renal Impairment [see Warnings and Precautions (5.6)]
- Rhabdomyolysis [see Warnings and Precautions (5.7)]
- Retinal Pathology in Rat [see Warnings and Precautions (5.8)]
- Events Reported with Dopaminergic Therapy [see Warnings and Precautions (5.9)]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice.
During the premarketing development of Mirapex ER tablets, patients with early Parkinson's disease were treated with Mirapex ER tablets, placebo, or immediate-release pramipexole tablets. In addition, a randomized, double-blind, parallel group trial was conducted in 156 early Parkinson’s disease patients (Hoehn & Yahr Stages I-III) to assess overnight switching of immediate-release pramipexole tablets to Mirapex ER tablets. In this latter study, concomitant treatment with stable doses of levodopa, monoamine oxidase B inhibitor (MAOB-I) drugs, anticholinergics, or amantadine, individually or in combination, was allowed. In a third trial, advanced Parkinson’s disease patients received Mirapex ER tablets, placebo, or immediate-release pramipexole tablets as adjunctive therapy to levodopa.
Early Parkinson's Disease
The most commonly observed adverse events (≥5% and more frequent than placebo) after 33 weeks of treatment with Mirapex ER tablets in the trial of early Parkinson’s disease patients were somnolence, nausea, constipation, dizziness, fatigue, hallucinations, dry mouth, muscle spasms, and peripheral edema.
Twenty four of 223 (11%) patients treated with Mirapex ER tablets for 33 weeks discontinued treatment due to adverse events compared to 4 of 103 (4%) patients who received placebo and approximately 20 of 213 (9%) patients who received immediate-release pramipexole tablets. The adverse event most commonly causing discontinuation of treatment with Mirapex ER tablets was nausea (2%).
Table 1 lists adverse events that occurred with a frequency of at least 2% with Mirapex ER and were more frequent than with placebo during 33 weeks of treatment in a double-blind, placebo-controlled study in early Parkinson's disease. In this study, patients did not receive concomitant levodopa; however, levodopa was permitted as rescue medication. Adverse events were usually mild (38%) or moderate (41%) in intensity.
| Body System/Adverse Event | Placebo | Mirapex ER | Immediate-Release Pramipexole |
|---|---|---|---|
| (n=103) | (n=223) | (n=213) | |
| % | % | % | |
| Nervous system disorders | |||
| Somnolence | 15 | 36 | 33 |
| Dizziness | 7 | 12 | 12 |
| Tremor | 1 | 3 | 3 |
| Balance disorder | 1 | 2 | 0 |
| Gastrointestinal disorders | |||
| Nausea | 9 | 22 | 24 |
| Constipation | 2 | 14 | 12 |
| Dry mouth | 1 | 5 | 4 |
| Vomiting | 0 | 4 | 4 |
| Upper abdominal pain | 1 | 3 | 4 |
| Dyspepsia | 2 | 3 | 3 |
| Abdominal discomfort | 0 | 2 | 1 |
| General disorders and administration site conditions | |||
| Fatigue | 4 | 6 | 6 |
| Peripheral edema | 4 | 5 | 8 |
| Asthenia | 2 | 3 | 1 |
| Musculoskeletal and connective tissue disorders | |||
| Muscle spasms | 3 | 5 | 3 |
| Psychiatric disorders | |||
| Hallucinations, including visual, auditory and mixed | 1 | 5 | 6 |
| Insomnia | 3 | 4 | 4 |
| Sleep attacks or sudden onset of sleep | 1 | 3 | 6 |
| Sleep disorder | 1 | 2 | 3 |
| Depression | 0 | 2 | 0 |
| Injury, poisoning and procedural complications | |||
| Fall | 1 | 4 | 4 |
| Vascular disorders | |||
| Orthostatic hypotension | 1 | 3 | 0 |
| Ear and labyrinth disorders | |||
| Vertigo | 1 | 4 | 2 |
| Metabolism and nutrition disorders | |||
| Increased appetite | 1 | 3 | 2 |
| Respiratory, thoracic and mediastinal disorders | |||
| Cough | 1 | 3 | 3 |
Because this study used a flexible dose titration design, it was not possible to assess the effects of dose on the incidence of adverse events.
Adverse events can initially occur in either the titration or maintenance phase. Some adverse events developed in Mirapex ER-treated patients during the titration phase and persisted (≥7 days) into the maintenance phase (i.e., Mirapex ER % - placebo % = treatment difference ≥2%); persistent adverse events were somnolence, nausea, constipation, fatigue, and dry mouth.
A double-blind, randomized, parallel group trial evaluated the tolerability of an overnight switch from immediate-release pramipexole tablets to Mirapex ER tablets at the same daily dose in 156 early Parkinson’s disease patients with or without levodopa. One of 104 patients switched from immediate-release pramipexole tablets to Mirapex ER tablets discontinued due to adverse events (vertigo and nausea).
Advanced Parkinson's Disease
The most commonly observed adverse events (≥5% and greater frequency than in placebo) during 18 weeks of treatment with Mirapex ER tablets in the trial of advanced Parkinson’s disease patients with concomitant levodopa were dyskinesia, nausea, constipation, hallucinations, headache, and anorexia.
Eight of 164 (5%) patients treated with Mirapex ER tablets for 18 weeks discontinued treatment due to adverse events compared to 7 of 178 (4%) patients who received placebo and 8 of 175 (5%) patients who received immediate-release pramipexole tablets. The most common adverse events leading to discontinuation of treatment with Mirapex ER tablets were nausea (1%) and hallucination (1%).
Table 2 lists adverse events that occurred with a frequency of at least 2% with Mirapex ER and were more frequent than with placebo during 18 weeks of treatment in patients with advanced Parkinson’s disease treated with Mirapex ER tablets. In this study, Mirapex ER tablets, immediate-release pramipexole tablets, or placebo was administered to patients who were also receiving concomitant levodopa. Adverse events were usually mild (32%) or moderate (17%) in intensity.
| Body System/Adverse Event | Placebo | Mirapex ER | Immediate-Release Pramipexole |
|---|---|---|---|
| n=178 | n=164 | n=175 | |
| % | % | % | |
| *18-week final analysis | |||
| Nervous system disorders | |||
| Dyskinesia | 8 | 17 | 18 |
| Headache | 3 | 7 | 4 |
| Dizziness (postural) | 1 | 2 | 3 |
| Gastrointestinal disorders | |||
| Nausea | 10 | 11 | 11 |
| Constipation | 5 | 7 | 6 |
| Salivary hypersecretion | 0 | 2 | 0 |
| Diarrhea | 1 | 2 | 1 |
| Psychiatric disorders | |||
| Hallucinations, including visual, auditory and mixed | 2 | 9 | 7 |
| Insomnia | 2 | 4 | 4 |
| Metabolism and nutrition disorders | |||
| Anorexia | 2 | 5 | 1 |
| Musculoskeletal and connective tissue disorders | |||
| Back pain | 1 | 2 | 3 |
Because this flexible dose study used a titration design, it was not possible to assess the effects of dose on the incidence of adverse events.
Adverse events can initially occur in either the titration or maintenance phase. Some adverse events developed in Mirapex ER-treated patients during the titration phase and persisted (≥7 days) into the maintenance phase (i.e., Mirapex ER % - placebo % = treatment difference ≥2%); persistent adverse events were dyskinesia and insomnia.
Laboratory Testing
During the development of Mirapex ER tablets, no systematic abnormalities on routine laboratory testing were noted. Therefore, no specific guidance is offered regarding routine monitoring; the practitioner retains responsibility for determining how best to monitor the patient in his or her care.
Other adverse events observed during clinical trials of immediate-release pramipexole tablets
Adverse events not listed above but reported on at least two occasions (one occasion if the event was serious) in clinical studies involving 2509 individuals who received pramipexole immediate-release tablets are listed below. The reported events are included without regard to determination of a causal relationship to pramipexole immediate-release tablets.
Blood and lymphatic system disorders: anemia, iron deficiency anemia, leukocytosis, leukopenia, lymphadenitis, lymphadenopathy, thrombocythaemia, thrombocytopenia
Cardiac disorders: angina pectoris, arrhythmia supraventricular, atrial fibrillation, atrioventricular block first degree, atrioventricular block second degree, bradycardia, bundle branch block, cardiac arrest, cardiac failure, cardiac failure congestive, cardiomegaly, coronary artery occlusion, cyanosis, extrasystoles, left ventricular failure, myocardial infarction, nodal arrhythmia, sinus arrhythmia, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia, ventricular fibrillation, ventricular extrasystoles, ventricular hypertrophy
Congenital, familial, and genetic disorders: atrial septal defect, congenital foot malformation, spine malformation
Ear and labyrinth disorders: deafness, ear pain, hearing impaired, hypoacusis, motion sickness, vestibular ataxia
Endocrine disorders: goiter, hyperthyroidism, hypothyroidism
Eye disorders: accommodation abnormalities, amaurosis fugax, blepharitis, blepharospasm, cataract, dacryostenosis acquired, diplopia, dry eye, eye hemorrhage, eye irritation, eye pain, eyelid edema, eyelid ptosis, glaucoma, keratitis, macular degeneration, myopia, photophobia, retinal detachment, retinal vascular disorder, scotoma, vision abnormalities, vision blurred, visual acuity reduced, vitreous floaters
Gastrointestinal disorders: abdominal distension, aphthous stomatitis, ascites, cheilitis, colitis, colitis ulcerative, dyspepsia, dysphagia, duodenal ulcer, duodenal ulcer hemorrhage, enteritis, eructation, fecal incontinence, gastric ulcer, gastric ulcer hemorrhage, gastritis, gastrointestinal hemorrhage, gastroesophageal reflux disease, gingivitis, haematemesis, haematochezia, hemorrhoids, hiatus hernia, hyperchlorhydria, ileus, inguinal hernia, intestinal obstruction, irritable bowel syndrome, esophageal spasm, esophageal stenosis, esophagitis, pancreatitis, periodontitis, rectal hemorrhage, reflux esophagitis, tongue edema, tongue ulceration, toothache, umbilical hernia
General disorders: chest discomfort, chills, death, drug withdrawal syndrome, face edema, feeling cold, feeling hot, feeling jittery, fever, gait disturbance, impaired healing, influenza-like illness, irritability, localized edema, edema, malaise, pitting edema, thirst
Hepatobiliary disorders: biliary colic, cholecystitis, cholecystitis chronic, cholelithiasis
Immune system disorders: drug hypersensitivity
Infections and infestations: abscess, acute tonsillitis, appendicitis, bronchiolitis, bronchitis, bronchopneumonia, cellulitis, cystitis, dental caries, diverticulitis, ear infection, eye infection, folliculitis, fungal infection, furuncle, gangrene, gastroenteritis, gingival infection, herpes simplex, herpes zoster, hordeolum, influenza, intervertebral discitis, laryngitis, lobar pneumonia, nail infection, onychomycosis, oral candidiasis, orchitis, osteomyelitis, otitis externa, otitis media, paronychia, pyelonephritis, pyoderma, sepsis, skin infection, tonsillitis, tooth abscess, tooth infection, upper respiratory tract infection, urethritis, vaginal candidiasis, vaginal infection, viral infection, wound infection
Injury, poisoning, and procedural complications: accidental falls, drug toxicity epicondylitis, road traffic accident, sunburn, tendon rupture
Metabolism and nutrition disorders: cachexia, decreased appetite, decreased weight, dehydration, diabetes mellitus, fluid retention, gout, hypercholesterolemia, hyperglycemia, hyperlipidemia, hyperuricemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, hypovitaminosis, increased creatine PK, metabolic alkalosis
Musculoskeletal and connective tissue disorders: bone pain, bursitis, fasciitis, flank pain, intervertebral disc disorder, intervertebral disc protrusion, joint effusion, joint stiffness, joint swelling, monarthritis, muscle rigidity, musculoskeletal stiffness, myasthenia, myopathy, myositis, nuchal rigidity, osteoarthritis, osteonecrosis, osteoporosis, pain in extremity, polymyalgia, rheumatoid arthritis, shoulder pain, spinal osteoarthritis, tendonitis, tenosynovitis, twitching
Neoplasms benign, malignant, and unspecified: abdominal neoplasm, adenocarcinoma, adenoma benign, basal cell carcinoma, bladder cancer, breast cancer, breast neoplasm, chronic lymphocytic leukemia, colon cancer, colorectal cancer, endometrial cancer, gallbladder cancer, gastric cancer, gastrointestinal neoplasm, hemangioma, hepatic neoplasm, hepatic neoplasm malignant, lip and/or oral cavity cancer, lung neoplasm malignant, lung cancer metastatic, lymphoma, malignant melanoma, melanocytic naevus, metastases to lung, multiple myeloma, oral neoplasm benign, neoplasm, neoplasm malignant, neoplasm prostate, neoplasm skin, neuroma, ovarian cancer, prostate cancer, prostatic adenoma, pseudo lymphoma, renal neoplasm, skin cancer, skin papilloma, squamous cell carcinoma, thyroid neoplasm, uterine leiomyoma
Nervous system disorders: ageusia, akinesia, amnesia, akathisia, anticholinergic syndrome, aphasia, brain edema, carotid artery occlusion, carpal tunnel syndrome, cerebral artery embolism, cerebral hemorrhage, cerebral infarction, cerebral ischemia, chorea, cognitive disorder, coma, convulsion, coordination abnormal, dementia, depressed level of consciousness, disturbance in attention, dizziness postural, dysarthria, dysgraphia, dystonia, extrapyramidal syndrome, facial palsy, grand mal convulsion, hemiplegia, hyperaesthesia, hyperkinesia, hyperreflexia, hyporeflexia, hypertonia, hypesthesia, hypotonia, lethargy, loss of consciousness, memory impairment, migraine, muscle contractions involuntary, myoclonus, narcolepsy, neuralgia, neuropathy, nystagmus, parosmia, psychomotor hyperactivity, sciatica, sedation, sensory disturbance, sleep phase rhythm disturbance, sleep talking, stupor, syncope vasovagal, tension headache, thinking abnormalities
Psychiatric disorders: affect lability, aggression, agitation, bradyphrenia, bruxism, suicide, delirium, delusions, delusional disorder persecutory type, disorientation, dissociation, emotional distress, euphoric mood, initial insomnia, libido increased, mania, middle insomnia, mood altered, nightmare, obsessive thoughts, obsessive-compulsive disorder, panic reaction, paranoid reaction, parasomnia, personality disorder, psychotic disorder, restlessness, sleep walking, suicidal ideation
Renal and urinary disorders: chromaturia, dysuria, glycosuria, hematuria, urgency, nephrolithiasis, neurogenic bladder, nocturia, oliguria, pollakiuria, proteinuria, renal artery stenosis, renal colic, renal cyst, renal failure, renal impairment, urinary frequency, urinary incontinence, urinary retention, urinary tract infection
Reproductive system and breast disorders: amenorrhea, breast pain, dysmenorrhea, epididymitis, gynaecomastia, impotence, menopausal symptoms, menorrhagia, metrorrhagia, ovarian cyst, priapism, prostatitis, sexual dysfunction, uterine hemorrhage, vaginal discharge, vaginal hemorrhage
Respiratory, thoracic, and mediastinal disorders: apnea, aspiration, asthma, choking, chronic obstructive pulmonary disease, dry throat, dysphonia, dyspnea exertional, epistaxis, haemoptysis, hiccups, hyperventilation, increased bronchial secretion, laryngospasm, nasal congestion, nasal dryness, nasal polyps, obstructive airways disorder, pharyngolaryngeal pain, pleurisy, pneumonia, pneumonia aspiration, pneumothorax, postnasal drip, productive cough, pulmonary embolism, pulmonary edema, respiratory alkalosis, respiratory distress, respiratory failure, respiratory tract congestion, rhinitis allergic, rhinorrhea, sinus congestion, sleep apnoea syndrome, sneezing, snoring, tachypnea, wheezing
Skin and subcutaneous tissue disorders: acne, alopecia, cold sweat, dermal cyst, dermatitis, dermatitis bullous, dermatitis contact, dry skin, ecchymosis, eczema, erythema, hyperkeratosis, livedo reticularis, night sweats, periorbital edema, petechiae, photosensitivity allergic reaction, psoriasis, purpura, rash erythematous, rash maculo-papular, rash papular, rosacea, seborrhea, seborrheic dermatitis, skin burning sensation, skin discoloration, skin disorders, skin exfoliation, skin hyperpigmentation, skin hypertrophy, skin irritation, skin nodule, skin odor abnormal, skin ulcer, urticaria
Vascular disorders: aneurysm, angiopathy, arteriosclerosis, circulatory collapse, deep vein thrombosis, embolism, hematoma, hot flush, hypertensive crisis, lymphoedema, pallor, phlebitis, Raynaud’s phenomenon, shock, thrombophlebitis, thrombosis, varicose vein
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of immediate-release pramipexole tablets, primarily in Parkinson’s disease patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to pramipexole tablets. Similar types of events were grouped into a smaller number of standardized categories using the MedDRA terminology: abnormal behavior, abnormal dreams, accidents (including fall), blackouts, cardiac failure, compulsive shopping, fatigue, hallucinations (all kinds), headache, hypotension (including postural hypotension), increased eating (including binge eating, compulsive eating, and hyperphagia), libido disorders (including increased and decreased libido, and hypersexuality), pathological gambling, pruritus, syncope, vomiting, and weight increase.
In a pharmacoepidemiological study, pramipexole use was associated with an increased risk of cardiac failure compared with non-use of pramipexole.
7 DRUG INTERACTIONS
No drug interaction studies were conducted with Mirapex ER tablets since the potential for drug interactions mainly depends on the active drug substance pramipexole and not the formulation. Data are available for the immediate-release pramipexole tablet formulation [see Clinical Pharmacology (12.3)].
Dopamine Antagonists
Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of Mirapex ER tablets.
Drug/Laboratory Test Interactions
There are no known interactions between pramipexole and laboratory tests.
8 USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Mirapex ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
When pramipexole was given to female rats throughout pregnancy, implantation was inhibited at a dose of 2.5 mg/kg/day [5 times the maximum recommended human dose (MRHD) on a mg/m2 basis]. Administration of 1.5 mg/kg/day of pramipexole to pregnant rats during the period of organogenesis (gestation days 7 through 16) resulted in a high incidence of total resorption of embryos. The plasma AUC in rats at this dose was 4 times the AUC in humans at the MRHD. These findings are thought to be due to the prolactin-lowering effect of pramipexole, since prolactin is necessary for implantation and maintenance of early pregnancy in rats (but not rabbits or humans). Because of pregnancy disruption and early embryonic loss in these studies, the teratogenic potential of pramipexole could not be adequately evaluated. There was no evidence of adverse effects on embryo-fetal development following administration of up to 10 mg/kg/day to pregnant rabbits during organogenesis (plasma AUC was 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with 0.5 mg/kg/day (approximately equivalent to the MRHD on a mg/m2 basis) or greater during the latter part of pregnancy and throughout lactation.
Nursing Mothers
A single-dose, radio-labeled study showed that drug-related material was present in rat milk at concentrations three to six times higher than in plasma at equivalent time points.
Studies have shown that pramipexole treatment resulted in an inhibition of prolactin secretion in humans and rats.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from pramipexole, a decision should be made as to whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The pharmacokinetics, safety, and efficacy of Mirapex ER tablets in pediatric patients have not been evaluated.
Geriatric Use
Pramipexole total oral clearance is approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours. In a placebo-controlled clinical trial of Mirapex ER tablets in early Parkinson’s disease, 47% of the 259 patients were ≥65 years of age. Among patients receiving Mirapex ER tablets, hallucinations were more common in the elderly, occurring in 13% of the patients ≥65 years of age compared to 2% of the patients <65 years of age.
Patients with Renal Impairment
The elimination of pramipexole is dependent upon renal function. Pramipexole clearance is extremely low in dialysis patients, as a negligible amount of pramipexole is removed by dialysis [see Dosage and Administration (2.2), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)].
9 DRUG ABUSE AND DEPENDENCE
Controlled Substance
Pramipexole is not a controlled substance.
Abuse and Dependence
Pramipexole has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. However, in a rat model of cocaine self-administration, pramipexole had little or no effect.
10 OVERDOSAGE
There is no clinical experience with significant overdosage. One patient took 11 mg/day of pramipexole for 2 days in a clinical trial for an investigational use. Blood pressure remained stable, although pulse rate increased to between 100 and 120 beats/minute. No other adverse events were reported related to the increased dose.
There is no known antidote for overdosage of a dopamine agonist. If signs of central nervous system stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdosage has not been assessed. Management of overdose may require general supportive measures along with gastric lavage, intravenous fluids, and electrocardiogram monitoring.
11 DESCRIPTION
Mirapex ER tablets contain pramipexole, a non-ergot dopamine agonist. The chemical name of pramipexole dihydrochloride is (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride monohydrate. Its empirical formula is C10 H17 N3 S • 2HCl • H2O, and its molecular weight is 302.26.
The structural formula is:
Pramipexole dihydrochloride is a white to off-white powder substance. Melting occurs in the range of 296°C to 301°C, with decomposition. Pramipexole dihydrochloride is more than 20% soluble in water, about 8% in methanol, about 0.5% in ethanol, and practically insoluble in dichloromethane.
Mirapex ER tablets, for oral administration, contain 0.375 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, or 4.5 mg of pramipexole dihydrochloride monohydrate. Inactive ingredients are hypromellose, corn starch, carbomer homopolymer, colloidal silicon dioxide, and magnesium stearate.
12 CLINICAL PHARMACOLOGY
Mechanism of Action
Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.
The precise mechanism of action of pramipexole as a treatment for Parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum. The relevance of D3 receptor binding in Parkinson’s di
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